The present invention relates to a new pharmaceutical dosage form for the transdermal administration of an active principle.
The 1980s saw the development of transdermal systems which are applied to a delimited area of the skin and which serve as a carrier or vehicle for one or more active principles, which are generally intended to exert a systemic action after release and passage through the cutaneous barrier.
These systems, generally referred to as xe2x80x9ctransdermal patchesxe2x80x9d, afford a number of advantages over the traditional dermatological forms such as ointments, salves, gels, solutions and lotions, namely:
direct and continuous entry into the general circulation,
elimination of the hepatic first-pass effect and/or of degradation in the digestive tract, with a consequent decrease in side effects,
extended duration of action,
maintenance of a constant level of active principles in the plasma,
increase in patient compliance through decrease in the frequency of dosage,
decrease in inter-individual variations,
control over the dose administered as a result of a matrix or membrane system with a reservoir,
production of a constant concentration of active principle during the period of the application.
Despite the degree of innovation provided by these systems, only a very small number of specialities exist today in this form. This is due to the fact that these devices demand:
a very sophisticated technology of manufacture,
few production sites which belong to a few large groups who have a monopoly of them,
this leads to a high cost of manufacture and to a substantial cost and sale price. These systems are, in actual fact, reserved for expensive products.
The present invention is directed towards providing new pharmaceutical dosage forms for the transdermal administration of an active principle
which are very simple to use, and do not require massive, complex and costly industrial plants,
which are multi-purpose; both from the standpoint of formulation and as regards the procedures for application when used,
which are advantageous from an economic standpoint with a lower production cost.
To this end, the subject of the present invention is a composition intended to form a film on the skin for the transdermal administration of an active principle, which comprises as liquid solution:
a) a lipophilic active principle
b) from 2.5 to 60% in weight, and advantagesouly from 2.5 to 25% by weight, of a silicone-based adhesive polymer composition
c) from 0 to 25% by weight, of an absorption promoter, and
d) from 25 to 95% by weight, and advantageously from 50 to 95% by weight, of volatile solvents comprising volatile silicones.
The subject of the present invention is also:
the use of a composition which comprises:
a) an active principle
b) from 2.5 to 60% by weight, and advantageously from 2.5 to 25% by weight, of a silicone) based adhesive polymer composition
c) from 0 to 25% by weight of an absorption promoter, and
d) from 25 to 95% by weight, and advantageously from 50 to 95% by weight, of volatile solvents comprising volatile silicones for the production of a film on a patient""s skin for the transdermal administration of the active principle;
a process for administering an active principle to a patient transdermally, which comprises the formation of a film on this patient""s skin by applying to the skin a liquid solution which comprises:
a) an active principle
b) from 2.5 to 60% by weight and advantageously from 2.5 to 25% by weight of a silicone-based adhesive polymer composition
c) from 0 to 25% by weight of an absorption promoter, and
d) from 25 to 95% by weight, and advantageously from 50 to 95% by weight, of volatile solvents comprising volatile silicones.
In the present invention, active principle denotes chiefly a medicinal product or substance having therapeutic properties.
These medicinal products are, in particular, lipophilic vitamins such as vitamins D and E and their derivatives, hormones such as calcitonin, steroids such as oestradiol and its esters, a progestogen (such as norethisterone) and prednisone, or nicotine.
The percentages of the active principles in the compositions of the invention clearly depend on the nature of the active principle. Generally, the percentages are from 0.01 to 10% by weight.
According to the invention, silicone-based polymer composition is understood to mean a composition containing silicone-based polymers or silicone-based copolymers.
These silicones, which will be designated according to the nomenclature of the CTFA (Cosmetic, Toiletry and Fragrance Association) Dictionary, comprise, in particular, polydimethylsiloxane oils or polydimethylsiloxane oils modified with ionic or nonionic organic groups.
As an example of polydimethylsiloxane oils, there may be mentioned dimethicones of formula: 
where n is an integer below 5,000, and dimethiconols, which are dimethyl silicones terminated with hydroxyl groups.
As an example of modified polydimethylsiloxanes, there may be mentioned dimethicone copolyols, which are polymers of dimethylsiloxane containing polyoxyethylene and/or polyoxypropylene side chains.
The silicone-based adhesive polymer composition preferably represents 2.5 to 12% and more advantageously from 2.5 to 10% of the weight of the composition,
The absorption promoters may be selected in particular, from propylene glycol, hexylene glycol, propylene glycol dipelargonate, glyceryl monoethyl ether, diethylene glycol, monoglycerides, monooleate of ethoxylated glycerides (with 8 to 10 ethylene oxide units), Azone (1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane, isopropylmyristate, octylmyristate, dodecyl-myristate, myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate, terpinol, 1-menthol, d-limonene, xcex2-cyclodextrin and its derivatives or surfactants such as polysorbates, sorbitan esters, sucrose esters, fatty acids, bile salts, or alternatively lipophilic and/or hydrophilic and/or amphiphilic products such as poly-glycerol esters, N-methylpyrrolidone, polyglycosylated glycerides and cetyl lactate.
The absorption promoter preferably represents from 5 to 25% of the weight of the composition.
As volatile silicone, it is possible to use polydimethylcyclosiloxanes, that is to say compounds of formula: 
where n is between 3 and 6 on average, and in particular compounds in which n=4 or 5, as well as linear polysiloxanes such as hexamethyldisiloxane or dimethicones of low molecular mass.
In addition to the volatile silicones it is also possible to use other solvents such as ethanol, isopropanol, chloroform, heptane, ethyl acetate, preferably in an amount representing up to 25% by weight, and more preferably up to 20% by weight of the compositions. Water should be avoided since water is not compatible with the polysiloxanes.
The composition according to the invention may be contained in a dispensing apparatus which delivers defined and reproducible doses of composition. For example, the dispensing apparatus delivers a drop of composition, and this drop may be spread on the skin using a brush or using a ball which is rolled over the skin.
The present invention finds an especially advantageous use for the transdermal administration of vitamin D3 (cholecalciferol).
Recent studies tend to show that all the populations of Western countries, and especially European countries, are lacking in Vitamin D in winter. The phenomenon is of less significance in the United States and in the Scandinavian countries which have a vitamin D3-enriched diet.
In general, hypovitaminosis has been observed in the elderly individuals of all countries, and manifests itself in an osteomalacia and abnormal phenomena in bone chemistry.
The causes of deficiency are:
quantitatively and qualitatively insufficient dietary intake: eggs, butter, liver, fatty fish, etc.
lack of sunshine, since cutaneous synthesis takes place under the effect of UV rays. This source of supply of natural vitamin D is strongly dependent on climatic conditions.
malabsorption syndrome: in elderly subjects, there is a decrease in the intestinal absorption of vitamin D as a result of the decrease in liver and kidney functions.
At the present time, the specialities available on the market are essentially presented in pharmaceutical dosage forms for the oral route and a few for administration by injection (IM). Now, the oral route is not always well assimilated, and administration by injection is not always accepted by elderly individuals.
The subject of the present invention is hence, more specifically, a liquid solution intended to form a film on the skin for the transdermal administration of vitamin D3 or a hydroxylated derivative of vitamin D3, and which comprises:
a) vitamin D3 or a hydroxylated derivative of vitamin D3 
b) from 5 to 60% by weight, and preferably from 9 to 12% by weight, of a silicone-based adhesive polymer composition
c) from 0 to 25% by weight of an absorption promoter, and
d) from 25 to 95% by weight and preferably from 65 to 85% by weight, of a volatile solvent comprising a volatile silicone.
The present invention relates also to a liquid solution intended to form a film on the skin for the transdermal administration of an active ingredient selected from oestrogens, progestogens and mixtures thereof, and which comprises:
a) an active ingredient selected from oestrogens, progestogens and mixtures thereof,
b) from 2.5 to 25% by weight of a silicone based adhesive polymer composition
c) from 0 to 25% by weight of an absorption promoter
d) from 35 to 55% by weight of a volatile silicone, and
e) from 0 to 35% by weight of a volatile polar solvent.
The polar solvent is in particular selected from ethanol, ethyl acetate and mixtures thereof and the composition contains advantageously 0 to 20% by weight of ethanol and 0 to 15% by weight of ethyl acetate.
Examples of compositions according ot the invention will be given below.